Innate immune regulation of infection tolerance

所有活着的有机体都有免疫反应来保护它们免受感染。我们认为这些免疫反应有两种基本方式：“抵抗”反应通过杀死入侵者来保护宿主，而“耐受”反应通过防止感染造成的损害来保护宿主。这两种类型的反应必须协同工作：没有耐受性的耐药不能让我们在许多病原体存在的情况下存活，而耐受不耐受将导致病原体的丰度和增殖增加，导致感染，我们的免疫系统将对此无能为力。许多耐药机制相对较好，但我们对感染耐受是如何起作用的知之甚少。例如，尽管耐受性已被认为是一种潜在的治疗干预措施，但我们仍然不知道耐受性通常是由免疫反应(“诱导性”耐受性)激活的，还是耐受性是一种预先存在的状态。我们也不知道耐受性和抵抗力是如何共同控制感染和保持宿主健康的。在我们的实验室里，我们研究了果蝇对细菌感染的免疫反应。果蝇的免疫反应在许多方面与人类和其他哺乳动物的免疫反应相似，但由于果蝇体型小，价格低廉，世代时间短，我们可以研究整个动物对感染的免疫反应，这是哺乳动物不可能做到的。我们最近发现，携带一种“抗药性”基因突变的果蝇在感染耐受性方面也存在严重缺陷：当这些突变型果蝇感染致病细菌时，它们的死亡时间明显快于非突变型果蝇，但在抗药性方面没有表现出差异(突变型和非突变型果蝇含有相同数量的细菌)。因此，这些果蝇的免疫反应表明，耐受性可能是一种诱导特征。这是非常令人兴奋的，因为它允许我们识别由该基因激活的耐受机制。我们提出的实验将集中在这种耐受效应的三个方面。首先，我们将测量突变和非突变果蝇在感染期间的代谢和行为差异。这一点很重要，因为代谢控制和行为被认为是耐受性的关键决定因素，但我们真的不知道耐受性和非耐受性宿主之间这两个方面有什么不同。其次，我们将测试相关基因在影响耐受性方面的作用，并确定这些基因在哪些组织中发挥作用，以促进感染耐受性。这一点很重要，因为它将使我们深入了解耐受性诱导的机制，并允许我们确定耐受性在多大程度上是由宿主遗传学决定的。最后，我们将利用这些信息和感染启动的基因信息，来确定耐受诱导的遗传机制。这一点很重要，因为它将让我们了解在宿主中促进耐受性的具体机制，而不是对耐药性的影响。这项工作最终可能导致提高感染者的耐受性的能力。促进耐受性的疗法将有助于让免疫系统或抗生素有时间发挥作用。因此，我们希望我们对果蝇感染生物学的分析将为我们提供最终对治疗人类疾病有用的信息。

All living organisms have immune responses to protect them from infections. We regard these immune responses as working in two basic ways: "resistance" responses protect the host by killing invaders, while "tolerance" responses protect the host by preventing damage caused by infection. These two types of response must work together: resistance without tolerance cannot keep us alive in the presence of many pathogens, while tolerance without resistance will result in an increase in both the abundance and proliferation of pathogens, leading to infections against which our immune systems will be defenseless . Many resistance mechanisms are relatively well-understood, but we know very little about how infection tolerance works. For example, even though tolerance has been cited as a potential therapeutic intervention, we still don't know whether tolerance is generally activated by immune responses ("inducible" tolerance), or if tolerance is a pre-existing state. We also don't understand how tolerance and resistance work together in controlling infections and keeping the host healthy.In our lab, we study the immune response of the fruit-fly Drosophila melanogaster to bacterial infection. The fruit-fly's immune response is similar in many ways to those of humans and other mammals, but because flies are small, inexpensive, and have a short generation time, we can study immune responses to infection in the whole animal in ways that are impossible in mammals. We have recently discovered that flies with a genetic mutation in a "resistance" gene also have a serious defect in infection tolerance: when these mutants are infected with pathogenic bacteria, they die significantly sooner than non-mutant flies, but show no difference in terms of resistance (mutants and non-mutants contain the same number of bacteria). Thus, the immune response of these flies suggests that tolerance may be an inducible trait. This is very exciting because it allows us to identify the mechanisms of tolerance that are being activated by this gene.The experiments we propose will focus on three aspects of this tolerance effect. First, we will measure metabolic and behavioural differences between mutant and non-mutant flies during infection. This is important because metabolic control and behaviour have been suggested to be critical determinants of tolerance, but we don't really have any grasp on how these two things would be different between tolerant and non-tolerant hosts. Second, we will test the roles of related genes in affecting tolerance, and determine which tissues these genes are functioning in to promote infection tolerance. This is important because it will give us insight into the mechanisms of tolerance induction, as well as allow us to determine to what extent tolerance is determined by host genetics. Finally, we will use this information and information on genes turned on by infection, to identify the genetic mechanisms of tolerance induction. This is important because it will let us know the specific mechanisms that can promote tolerance in the host, separate from effects on resistance.This work may ultimately lead to the ability to promote tolerance in people with infections. Therapies that promote tolerance would be useful to allow the immune system or antibiotics time to work. Thus, we hope that our analyses of infection biology in fruit flies will give us information that will ultimately be useful in the treatment of human disease.